The active ingredient in KALYDECO® tablets is Ivacaftor, which has the following chemical name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4oxoquinoline-3-carboxamide. Its molecular formula is C24H28N2O3 and its molecular weight is 392.49. Ivacaftor has the following structural formula:

Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL). Due to poor aqueous solubility, extensive formulation efforts were required and resulted in a spray-dried dispersion of Ivacaftor suitable for oral administration. KALYDECO® containing the spray-dried dispersion of Ivacaftor is available as a light blue capsule-shaped, film-coated tablet for oral administration containing 150 mg of Ivacaftor. Each tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein.
After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (tmax) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10,600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 12-hour dosing, steady-state plasma concentrations of Ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.
The exposure of Ivacaftor increased approximately 2-to 4-fold when given with food containing fat. Therefore, KALYDECO® should be administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, and cheese pizza. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.
The mean apparent volume of distribution (Vz/F) of Ivacaftor after a single dose of 275 mg of KALYDECO® in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.
Ivacaftor is extensively metabolized in humans. In-vitro and clinical studies indicate that Ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of Ivacaftor in humans. M1 has approximately one-sixth the potency of Ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of Ivacaftor and is not considered pharmacologically active.
Following oral administration, the majority of Ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of Ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose. The mean apparent clearance (CL/F) of Ivacaftor was similar for healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
Lumacaftor is one of the active ingredients in ORKAMBI® tablets, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3 -benzodioxol-5-yl)cyclopropyl]carbonyl}amino-3-methypyridin-2-yl]benzoic acid. The molecular formula for lumacaftor is C24H18F2N2O5. The molecular weight for Lumacaftor is 452.41. The structural formula is:

Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL).
ORKAMBI® is available as a pink, oval-shaped, film-coated tablet for oral administration containing 200 mg of Lumacaftor and 125 mg of Ivacaftor. Each ORKAMBI® tablet contains 200 mg of Lumacaftor and 125 mg of Ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. In-vitro studies have demonstrated that Lumacaftor acts directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.
Following multiple oral dose administrations of Lumacaftor, the exposure of Lumacaftor increased roughly proportionally with dose from 50 to 1000 mg qd. In subjects with CF, the Lumacaftor Cmax and AUC also increases approximately proportional with the dose over the Lumacaftor 25 mg qd to 400 mg q12h dose range. The exposure of Lumacaftor increased approximately 1.6-to 2.0-fold when given with fat containing food. The median (range) time of the maximum concentration (tmax) is approximately 4.0 (2.0, 9.0) hours in the fed state.
Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with cystic fibrosis (CF) in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L.
The half-life of Lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of Lumacaftor was estimated to be 238 L/hr (29.4%) for patients with CF.
Lumacaftor is not extensively metabolized in humans with the majority (51%) of Lumacaftor excreted unchanged in the feces. There was minimal elimination of Lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). In-vitro and in vivo data indicate that Lumacaftor is mainly metabolized via oxidation and glucuronidation.
Lumacaftor has low aqueous solubility and high permeability assessed via the colorectal adenocarcinoma (Caco-2) cell system. Although pH-dependent solubility was observed, the Lumacaftor drug substance is practically insoluble in water and buffer solutions of pH 1.0 to pH 8.0. Therefore, Lumacaftor is suggested to be a BCS Class 2 (low solubility/high permeability) compound.
Since Lumacaftor is considered a BCS class II, the drug substance was jet-milled early in development to reduce the particle size and potentially improve bioavailability. Based on these studies a control on Lumacaftor particle size in the drug substance specification was established.
Various formulations have been used in the development of Lumacaftor alone and in combination which includes suspension, capsules and tablets. Comparative exposure of the different formulations of Lumacaftor was seen in single dose studies in healthy volunteers. Exposure of the suspension is lower than that seen for capsules and tablets. Early clinical studies were conducted with the co-administration of both Ivacaftor and Lumacaftor. A cross-over study (007) was conducted to evaluate the relative bioavailability of the fixed dose combination tablet as compared to the separate tablets. The tablet and FDC appear to be bioequivalent, and the only parameter that did not meet standard bioequivalence criteria is the Cmax of Ivacaftor (GLSMR [90% CI]—1.20 [1.09, 1.33]). However, for practical purposes this is acceptable and the PK results from tablet formulation can be considered applicable to the FDC as well.
When a single dose of Lumacaftor/Ivacaftor was administered with fat-containing foods, Lumacaftor exposure was approximately 2 times higher and Ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.
Following multiple oral dose administration of Lumacaftor in combination with Ivacaftor, the exposure of Lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) tmax of Lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.
Following multiple oral dose administration of Ivacaftor in combination with Lumacaftor, the exposure of Ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The median (range) tmax of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state.
The main medical concerns surrounding the administration of Ivacaftor and Lumacaftor are related to the positive food effect both compounds exhibit which does not allow the precise administration of the current formulations. This is extensively true for pediatric patients where the current, fix dose tablet formulation does not allow the administration of the compound to children.
In order to overcome the problems associated with prior conventional formulations and available drug delivery systems containing Ivacaftor in combination with Lumacaftor, novel pharmaceutical composition comprising complex formulations of Ivacaftor, or salts or derivatives thereof, together with complexation agents and pharmaceutically acceptable excipients in combination with complex formulations of Lumacaftor, or salts or derivatives thereof, together with complexation agents and pharmaceutically acceptable excipients were prepared. Novel pharmaceutical compositions are characterized by instantaneous redispersibility, increased apparent solubility compared to KALYDECO® and ORKAMBI® like formulations, instantaneous dissolution, increased apparent permeability compared to KALYDECO® and ORKAMBI® like formulations that exhibits no food effect which allows the precise dosing the active ingredients.